The epithelial lining of air spaces of the human respiratory system provides a crucial barrier between inspired gas and pulmonary blood flow. By virtue of its large surface area, delicate membranes and anatomic location, the epithelial barrier is vulnerable to damage by inhaled toxic substances and attack by infectious agents. The cell wall-less bacterium, Mycoplasma pneumoniae (whose genome is completely sequenced), is a common bacterial pathogen of the human respiratory tract. It causes a range of acute and chronic illnesses, including tracheobronchitis, pneumonia and other airway pathologies as well as extrapulmonary manifestations, such as joint, CNS and cardiovascular involvement. This microorganism exhibits a flask-like appearance and adheres to respiratory cell surfaces via a unique tip-like terminal organelle. In general, bacterial adherence is a complex process involving multiple interactions and molecular cross-talk between the microbe and target cell. We have been investigating mechanisms of cytadherence of M. pneumoniae and other mycoplasmas, and our recent studies indicate that various components in the airway microenvironment contribute to mycoplasma-respiratory cell interactions and subsequent tissue colonization. Delineating the role of such environmental components in the infectious process of mycoplasmas, particularly M. pneumoniae, is a major objective of this proposal. We will focus on understanding how fibronectin (FN) and surfactant protein A (SP-A) influence the mycoplasma-airway cell interplay, as these host proteins exist abundantly in the respiratory tract. These proteins play several roles including i) modulating alveolar macrophages in enhanced phagocytosis of invading bacteria; and ii) assisting bacteria (particularly FN) in binding to non-phagocytic cells. We have discovered the presence of FN- and SP-A binding proteins in M. pneumoniae, and we intend to clarify the role of these proteins as mediators of mycoplasma- airway cell interactions. Thus, the proposed study is expected to provide new insights concerning mycoplasma parasitic mechanisms which, together with the existing knowledge base concerning mycoplasma cytadherence, will broaden our overall understanding of mycoplasma pathogenesis and virulence determinants. Ultimately, these studies should identify new therapeutic strategies to control mycoplasma infections in humans.